Derivatives of acetic acid for the alleviation of hyperlipemia

ABSTRACT

The compounds are of the class of bis-(4-trifluoromethylphenoxy) acetic acid compounds, e.g., bis-(4-trifluoromethylphenoxy)acetic acid 1-methyl-4-piperidyl ester. The compounds are useful as hypocholesteremic/hypolipemic agents.

United States Patent [151 3,683,086 Griot 51 Aug. 8, 1972 [54] DERIVATIVES OF ACETIC ACID FOR 3,448,105 6/ 1969 Griot ..260/246 THE ALLEVIATION OF 3,448,1 1O 6/1969 Griot ..260/294.3 HYPERLIPEMIA 3,452,081 6/ 1969 Sprague et a1. ..260/473 [72] Inventor: Rudolf G. Griot, Florham Park, NJ 3,454,581 7/ 1969 Griot ..260/294.3 [73] Assignee: Sandoz Wander, Inc. OTHER PUBLICATIONS [22] Filed: July 13, 1970 Brunet et a1., Bull. Soc, Chim., France, 5, 383- 7 (1964) mm 61,032 Yale, J. Med. Chem., 1 2 121- 33 1959 7 Related Application Data Primary Examiner-Jerome D. Goldberg [62] Division of Ser. No. 653,350, July 14, 1967, Attorney-Gerald D. Sharkin and Frederick H. Wein- Pat. No. 3,546,229. feldt [52] US. Cl. ..424/267, 424/244, 424/274 [57] ABSTRACT [51] Int. Cl. ..A6lk 27/00 w The compounds are of the class of b1s-(4- [58] Field of Search ..424/267, 274, 244 trifluoromethylphenoxy) acetic acid compounds eg" bis-(4-trifluoromethylphenoxy)acetic acid 1-methyl-4- [56] References Cited piperidyl ester. The compounds are useful as UNITED STATES PATENTS hypocholesteremic/hypolipemic agents.

3,332,957 7/ 1967 Bencze ..260/294.3 12 Claims, No Drawings DE V F ACETIC ACID OR THE and in the presence of an alkali metal alkoxide, such as A L Y I sodium methoxide or sodium ethoxide. The reaction is This application is a dlvlslon 0f 653,350, conveniently effected at an elevated temperature,

filed y l9 67,1}0W P preferably the reflux temperature of the system. The This applleailen a division of 653350 5 desired product is readily recovered in conventional filed July 14, 1967, now US. Pat. No. 3,546,229. manner,

This invention relates to derivatives of acetic acid. in I the alternative process, i 4- p P e the mvemlon P to easle esters of e acetic acid (IV) is converted to the corresponding acid l y p e y) P acid- The halide (V) by reaction with thionyl chloride or other also relates to intermediates which are useful in prepar to suitable reagent commonly used for this purpose ing the above compoundsthionyl bromide, phosphorus pentachloride and The compounds of the present mvemlon may be phosphorus pentabromide. The reaction is conrepresemed structurally as follows: veniently carried out in a suitable inert organic solvent l 5 and at room temperature C.) or elevated tempera- Y I tures up to reflux temperature of the system. However,

wherein the use of a solvent is not necessary since an excess of R represents a basic alcohol residue of the formula: P halide reagent can be employed for this f It 18 generally preferred to carry out the reaction in the Q 2o presence of a catalytic amount of dimethylformamide.

I The reaction of the thus-obtained acid halide with the R1 appropriate alcohol or alcoholate is conveniently efthe point of attachment of the heterocyclic ring fected in a suitable lnertorgamc solvent, e.g., benzene, being at any one of the available positions; toluene, chloroform and diethyl ether, and at room R represents lower alkyl, preferably containing from temperature or below The reaction if desirefi one to foulcarbon atoms eflg', methyl, ethyl, can be carried out at elevated temperature; however, in

propyland b such instances, external cooling should be provided n represents a h l number f f 0 to 4 inclw since the reaction is highly exothermic. Preferably the Sive; and reaction is carried out at a temperature of from about n represents a whole number greater than 3 and less -l to about Where the free alcohol is p y than 6,i.e.,4or 5. it is desirable to provide a means for taking up the The term TFMphenoxy as used h r i ft liberated hydrogen halide. This can be accomplished denotes trifluoromethylphenoxy. by employing an excess of the alcohol or by carrying The above compounds are p ed b ti 3 out the reaction in the presence of an alkali metal carlower alkyl ester of bis-(4TFMphenoxy)ac ti id or bonate, e.g., potassium carbonate, or suitable inert a di(lower)alk l ester of bi -(4-TFM h l i base, e.g., pyridine. Where an alcoholate is used, the alacid with an appropriate alcohol. Alternatively, the kali metal Salts. p larly the dium and potassium compounds may be prepared by converting bis-(4- salts, are preferred. The desired product thus obtained TFMphenoxy)acetic acid to its corresponding acid haiS readily e overed in Conventional manner. lide and thenreacting the latter with an appropriate al The monoand di-alkyl esters (II and Ill) employed cohol or alcoholate. These processes are illustrated by as Sta t ng materia s are readily prepared by reacting the following reaction scheme: I sodium 4-trifluoromethylphenolate (prepared from po0 (F c-Q-o 00 9 (F30 Q 0 one R a A c c R ROH (F1Co -c11co011 ROH \(or Alcoholate) (mo -0 01100011 (F3C-0 QCHO 0x IV v wherein trifluoromethylphenol and sodium hydride) with a R" represents lower alkyl, preferably containing lower alkyl dichloroacetate or di(lower)alkyl from one to four carbon atoms, e.g., methyl, ethyl, dibromomalonate, respectively. The reaction is readily propyl and butyl; carried out in a suitable inert organic solvent, e.g., X represents halo having an atomic weight of from dimethylacetamide, diethylacetamide and dimethylfor- 35 to 80, i.e., chloro or bromo; and mamide, and at room temperature or elevated tem- R is as defined above. perature (which should not exceed about C. when The reaction of the monoor di-alkyl ester (II or III) it is desired to prepare the esters of formula III). with the appropriate alcohol is carried out in a suitable The bis-(4-TFMphenoxy)acetic acid (IV), employed inert organic solvent, e.g., benzene, toluene and xylene, as the starting material for the alternative process described above, can be readily prepared in conventional manner from either the monoor di-alkyl ester (II or Ill) by reacting the same in an aqueous, inert organic solvent, with a strong base, at room temperature. The base is preferably one which will yield a water soluble salt of the desired acid, e.g., sodium hydroxide and potassium hydroxide. The acid then is obtained by simply treating the thus-obtained salt with a mineral acid, such as hydrochloric acid, in conventional manner. The acid (IV) can also be prepared by decarboxylating the free malonic acid obtained from the dialkylester (III) in conventional manner.

Many of the alcohols employed as starting materials are known and can be prepared as described in the literature. Such others which may not be specifically known can be prepared from available materials in analogous manner. The alcoholates can be prepared from the corresponding alcohols in conventional manner.

Certain of the compounds of Formula I have asymmetric centers and therefore exist as optical isomers. The respective isomers can be readily separated by conventional techniques or they can be selectively prepared employing the desired isomeric form of the alcohol reactant and accordingly are included within the scope of this invention.

The compounds of the present invention (Formula I) are useful because they possess pharmacological activity in animals. In particular, the compounds possess marked hypocholesteremic activity and can be used as hypocholesteremic/hypolipemic agents.

For such usage, the compounds may be admixed with conventional pharmaceutical carriers, and other adjuvants, if necessary, and administered orally in such forms as tablets, elixirs, suspensions or solutions. Furthermore the compounds may be similarly administered in the form of their non-toxic pharmaceutically acceptable acid addition or quaternary salts. Such salts do not materially differ from the free base in their pharmacological effects and are included within the scope of the invention. The acid addition salts are readily prepared by reacting the base with pharmacologically acceptable acids in conventional manner. Representative of such salts are the mineral acid salts such as the hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts such as the benzoate, acetate, maleate, ptoluenesulfonate, benzene-sulfonate and the like. Similarly, the quaternary salts are prepared by reacting the base with pharrnacologically acceptable quatemizing agents in conventional manner. Exemplary of the quaternary salts are those derived from common quaternizing agents such as straight-chain lower alkyl halides wherein the lower alkyl group preferably contains from one to four carbon atoms and the halide substituent is either chloride, bromide or iodide, e.g., methyl bromide, methyl chloride, ethyl bromide, methyl iodide and ethyl iodide, and straight-chain di- (lwer)alkyl sulfates, e.g., dimethyl sulfate.

For the above-mentioned use, the dosage administered will, of course, vary depending on the compound employed. However, in general, satisfactory results are obtained when administered at a daily dosage of from about 4 milligrams to about 30 milligrams per kilogram of animal body weight, preferably given in divided doses, 2 to 4 times a day, or in sustained release form. For most mammals, e.g., primates, the administration of from about 0.25 grams to about 2 grams of the compound in divided doses of from about 62.5 milligrams to about 1,000 milligrams 2 to 4 times a day, is adequate for the treatment of hypercholesteremia/hyperlipemia. A representative formulation suitable for oral administration is a tablet (prepared by standard tabletting techniques) and containing, by weight, 50 parts of bis-(4- trifluoromethylphenoxy) acetic acid l-methyl-4- piperidyl ester (as the free base), 2 parts of tragacanth, 39.5 parts of lactose, 5 parts of corn starch, 3 parts of talcum and 0.5 parts of magnesium stearate.

As noted hereinabove certain of the compounds of formula I exist as optical isomers. In some instances, enhanced activity or other beneficial attributes may be found with respect to a particular isomer and in such instances administration of such isomer may be preferred.

The intermediate compounds of structural formulae II and IV also possess hypocholesteremic activity and can be used as hypocholesteremic/hypolipemic agents. They can be administered in the same manner and at the same dosage levels as indicated for compounds of formula I hereinabove.

The compound of formula IV may be utilized either as the free acid or a non-toxic pharmaceutically acceptable salt thereof can be employed. Representative of non-toxic pharmaceutically acceptable salts are aluminum salts, the non-toxic alkali metal salts, e.g., potassium and sodium salts, the non-toxic alkaline earth metal salts, e.g., magnesium and calcium salts, the ammonium salts and salts of the non-toxic organic bases, e.g., ethanol-amine salts.

The following examples show representative compounds contemplated by the present invention and the manner in which said compounds are made. However, it is to be understood that the examples are intended for the purpose of illustration only and are not intended as in any way limiting the scope of the invention.

EXAMPLE 1 Bis-(4-trifluoromethylphenoxy )acetic acid Step A. Preparation of bis(4- trifluoromethylphenoxy)malonic acid diethyl ester 6.7 g. of 56.7 percent sodium hydride in mineral oil is washed with dry, low boiling petroleum ether. The washed sodium hydride is suspended in ml of dimethylacetamide and the obtained suspension is then cooled to 0. To the thus-cooled suspension is added 25.5 g of p-trifluoromethylphenol in 25 ml by volume of dimethylacetamide at such a rate that the temperature thereof does not exceed 10 (external cooling with an ice/salt bath being employed as necessary).

After all of the p-trifluoromethylphenol is added, the mixture is stirred for an additional hour. The mixture is removed from the cooling bath, and 23.8 g of diethyldibromomalonate added thereto fairly rapidly, allowing the temperature to rise to about 32. Stirring is continued for 88 hours.

I The mixture is then concentrated by evaporating in vacuo until 941 of the solvent is removed. 1500 ml of ethylacetate is then added to the resulting concentrate which is then washed twice with 1,500 ml portions of water and then washed twice with 750 ml portions of 2N (aq) sodium hydroxide. The thus-washed organic phase is dried over anhydrous magnesium sulfate, the dried organic phase filtered and the filtrate evaporated to obtain bis-(4-trifluoromethylphenoxy)malonic acid diethyl ester, mp 535 to 545; bp 134 l36/0.05 mm.

Step B. Preparation of bis-(4- trifluoromethylphenoxy)malonic acid precipitated barium salt is separated by filtering and dried at 60 C under vacuum for 3 hours.

A suspension of 16.19 g (0.02895 mol) of the barium salt of bis-(4-trifluoromethylphenoxy) malonic acid in 200 ml of methanol and 5 g of diatomaceous earth (Celite) is prepared and while stirring at C, is acidified by dropwise addition of a solution of 2.97 g of concentrated sulfuric acid (95.0 to 95.5 percent) in 3 ml, of water to hydrolyze the barium salt. The stirring of the mixture is continued at ambient temperatures for an additional 20 minutes. The mixture is filtered to remove solids from the solvent phase which contains the bis-(4-trifluoromethylphenoxy)malonic acid in the free acid form. The thus-separated solids are washed with 100 ml of ethyl acetate. The ethyl acetate phase is combined with the filtrate and the solvents removed by evaporation under vacuum (water aspirator) to obtain an oily residue. The oily residue is dissolved in 100 ml of ethyl acetate and washed twice with saturated aqueous sodium chloride. The organic phase is dried over anhydrous magnesium sulfate and then evaporated under vacuum to obtain an oily residue. The oily residue is washed thrice with 70 m1 portions of petroleum ether at 30 to 60 C resulting in solidification thereof. The thus-obtained bis-(4- trifluoromethylphenoxy)malonic acid melts with decomposition at 155 to 156.5 C and on refining by recrystallization from hexane-ethyl acetate (10:1) melts with decomposition at 157 to 158 C.

Step C. Preparation of bis-(4- trifluoromethylphenoxy)acetic acid 7.3 g (0.01725 mol) of bis-(4- trifluoromethylphenoxy) malonic acid is dissolved in a solution of 1.93 g (0.0345 mol) potassium hydroxide in 20 ml of water. To the solution is added 60 ml of 2- methoxy-ethoxyethanol and the mixture refluxed for 4 hours by heating with an oil bath maintained at 170 C. The water is then substantially removed from the mix ture by boiling off under atmospheric pressure; the mixture is heated for an additional 15 minutes at 190 C. The 2-methoxy ethoxyethanol is then substantially removed by evaporation under a water aspirator at C. to obtain the crude potassium salt of bis-(4- trifluoromethylphenoxy)acetic acid. The crude potassium salt of bis-(4-trifluoromethylphenoxy)acetic acid is dissolved in ml of water, the solution treated with charcoal, and then filtered through diatomaceous earth (Celite). The thus-treated solution is then acidified with 18 ml of 2N HCl resulting in the separation of crude bis-(4-trifluoromethylphenoxy)acetic acid as oil which solidifies. The crude bis-(4- trifluoromethylphenoxy) acetic acid is collected by filtration and then dissolved in 100 ml. of ethyl acetate. The ethyl acetate solution is washed twice with 50 ml portions of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under vacuum to obtain an oily residue which solidifies upon scratching The solid mass is washed with 50 m1 of petroleum ether at 30 to 60 C. to obtain bis-(4- trifluoromethylphenoxy)acetic acid, mp to 123 C, which on recrystallization from cyclohexanebenzene (5:1) has a melting point of 127 to l28.5 C.

EXAMPLE 2 Bis-(4-trifluoromethylphenoxy)acetic acid 1-methyl-4- piperidyl ester A mixture of 2.5 g (0.00657 mol) of bis-(4- trifiuoromethylphenoxy)acetic acid, 100 ml of anhydrous diethyl ether, 0.1 ml, of dimethyl formamide and 2 g (0.0168 mol) of thionyl chloride are refluxed in a vessel for 4 hours, while swept with a stream of nitrogen gas to carry off hydrogen chloride formed during the reaction. The reaction mixture is evaporated on a rotary evaporator under water aspiration at 45 C to obtain an oily residue. The oily residue is dissolved in 60 ml of carbon tetrachloride, the solution dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum to remove the solvent to obtain bis-( 4-trifluoromethylphenoxy) acetyl chloride.

To a solution of 1.49 g (0.0129 mol) 1-methy1-4- hydroxypiperidine in 50 ml of anhydrous diethyl ether at 0 C, is added dropwise, with stirring, a solution of 2.57 g (0.00645 mol) bis-(4-trifluoromethylphenoxy)acetyl chloride in 25 m1 of anhydrous diethyl ether and the mixture cooled during the addition to maintain the temperature at 0 to 5 C. A white solid begins to precipitate, and stirring is continued at 20 C for 18 hours. The white solid (essentially 1-methyl-4-hydrox ypiperidine hydrochloride) is removed by filtration. The filtrate is washed first 50 ml of ice cold 10 percent aqueous sodium bicarbonate, then with 30 ml of saturated aqueous sodium chloride. The organic phase is dried over anhydrous magnesium sulfate and then evaporated to obtain an oily residue. The oily residue is dissolved in 20 ml. of chloroform and the chlorofonn solution placed on silica gel held in a sintered glass filter funnel. Impurities are removed by eluting with 175 ml of chloroform and the product is recovered by eluting with 400 m1 of ethyl acetate. The ethyl acetate solution is evaporated under vacuum to obtain bis-(4- trifluoromethylphenoxy )acetic acid l-methyl-4- piperidyl ester as the free base.

0.977 g. (0.00205 mol) of bis-(4- trifluoromethylphenoxy)acetic acid l-methyl-4- piperidyl ester are added to 0.238 g (0.00205) of fumaric acid in 10 ml. of isopropanol to form the fumaric acid addition salt of bis-(4-trifluoromethylphenoxy)acetic acid l-methyl-4-piperidyl ester, which on recrystallizing twice from 5 ml, isopropanol and charcoal has a melting point of 127 to 130 C.

What is claimed is:

1. An orally administrable pharmaceutical composition for use in the alleviation of hyperlipemia in mammals comprising a hyperlipemia alleviating effective amount of a compound selected from the group consisting of a basic ester of the formula:

and the non-toxic pharmaceutically acceptable salts thereof, wherein R represents R represents lower alkyl;

n represents a whole number of from to 4, inclusive; and

n represents a whole number greater than 3 and less than 6 as an active ingredient thereof, and an orally administrable pharmaceutically acceptable carrier.

2. A composition of claim 1, wherein the compound is present in an amount sufficient to provide a daily dosage of from about 250 milligrams to about 2,000 milligrams.

3. A composition of claim 1, wherein the compound is the fumaric acid addition salt of bis-(4- trifluoromethylphenoxy) acetic acid l-methyl-4- piperidyl ester.

4. A composition of claim 2, wherein the compound is bis(4-trifluoromethylphenoxy) acetic acid l-methyl- 4-gipgridyl ester.

n orally administrable pharmaceutical composition as defined in claim 1, in unit dose form, wherein said compound is present in an amount of from about 62.5 milligrams to about 1,000 milligrams.

6. A composition of claim 5, wherein the carrier is solid.

7. A composition of claim 6, wherein the compound is the fumaric acid addition salt of bis-(4- trifluoromethylphenoxy) acetic acid l-methyl-4- piperidyl ester.

8. A composition of claim 6, wherein the compound is bis-(4-trifluoromethylphenoxy) acetic acid l-methyl- 4-piperidyl ester.

9. A method for the alleviation of hyperlipemia in a mammal which comprises orally administering to said mammal a hyperlipemia alleviating effective amount of a compound selected from the group consisting of a basic ester of the formula:

and the non-toxic pharmaceutically acceptable salts thereof, wherein R, R, n and n are as defined in claim 1.

10. A method of claim 9, wherein the compound is administered in an amount sufficient to provide a daily dosage of from about 250 milligrams to about 2,000

milligrams.

11. A method of claim 10, wherein the compound is the fumaric acid addition salt of bis-(4- trifluoromethylphenoxy) acetic acid l-methyl-4- piperidyl ester.

12. A method of claim 10, wherein the compound is bis-(4-trifluoromethylphenoxy) acetic acid l-methyl-4- piperidyl ester. 

2. A composition of claim 1, wherein the compound is present in an amount sufficient to provide a daily dosage of from about 250 milligrams to about 2,000 milligrams.
 3. A composition of claim 1, wherein the compound is the fumaric acid addition salt of bis-(4-trifluoromethylphenoxy) acetic acid 1-methyl-4-piperidyl ester.
 4. A composition of claim 2, wherein the compound is bis(4-trifluoromethylphenoxy) acetic acid 1-methyl-4-piperidyl ester.
 5. An orally administrable pharmaceutical composition as defined in claim 1, in unit dose form, wherein said compound is present in an amount of from about 62.5 milligrams to about 1,000 milligrams.
 6. A composition of claim 5, wherein the carrier is solid.
 7. A composition of claim 6, wherein the compound is the fumaric acid addition salt of bis-(4-trifluoromethylphenoxy) acetic acid 1-methyl-4-piperidyl ester.
 8. A composition of claim 6, wherein the compound is bis-(4-trifluoromethylphenoxy) acetic acid 1-methyl-4-piperidyl ester.
 9. A method for the alleviation of hyperlipemia in a mammal which comprises orally administering to said mammal a hyperlipemia alleviating effective amount of a compound selected from the group consisting of a basic ester of the formula: and the non-toxic pharmaceutically acceptable salts thereof, wherein R, R1, n and n'' are as defined in claim
 1. 10. A method of claim 9, wherein the compound is administered in an amount sufficient to provide a daily dosage of from about 250 milligrams to about 2,000 milligrams.
 11. A method of claim 10, wherein the compound is the fumaric acid addition salt of bis-(4-trifluoromethylphenoxy) acetic acid 1-methyl-4-piperidyl ester.
 12. A method of claim 10, wherein the compound is bis-(4-trifluoromethylphenoxy) acetic acid 1-methyl-4-piperidyl ester. 